PROJECT II: Sex Differences in Orexin and Oxytocin Mediation of Cocaine-seeking (See) Sex and gender differences have been reported in drug addiction for various drugs of abuse and across various stages of the addiction process. Moreover, cocaine seeking in females is closely linked to specific phases of the estrous cycle. Building on our previous discoveries of sex differences and hormonal influences in reinstatement to cocaine seeking, this project will examine two key neuropeptide substrates, orexin and oxytocin, that may underiie sex and estrous cycle-dependent differences in cocaine taking and reinstatement of cocaine seeking. Our broad hypothesis is that sex differences in cocaine seeking depend upon sexual dimorphisms in the orexin and oxytocin systems. The proposed studies will assess brain region specific changes in orexin and oxytocin, and test systemic and site directed receptor modulation of these peptide systems on cocaine seeking in males and females. The studies comprise a multifaceted neurobiological approach that complements the clinical SCOR projects that focus on gender differences and relapse in drug-dependent women and men, including the relationship of ovarian hormones to drug seeking. In addition, this project will integrate with the preclinical model of cocaine addiction proposed in Project 3 focused on the role of norepinephrine and corticotrophin-releasing factor (CRF) in males and females. RELEVANCE (See instructions): We will characterize fundamental sex and estrous cycle dependent differences in cocaine addiction and the role of two key neuropeptides, orexin and oxytocin, using an animal model closely linked with important clinical issues both conceptually (e.g., sex and ovarian cycle differences associated with cocaine addiction) and methodologically (e.g., analogous treatment with oxytocin). Providing relevant data on the neurobiology of cocaine addiction in males and females will guide future treatment approaches in human cocaine addicts.